Cross-sectional and longitudinal associations of Iron biomarkers and cardiovascular risk factors in pre- and postmenopausal women: leveraging repeated measurements to address natural variability.

BACKGROUND: The association between iron biomarkers and cardiovascular disease risk factors (CVD-RFs) remains unclear. We aimed to (1) evaluate the cross-sectional and longitudinal associations between iron biomarkers (serum ferritin, transferrin saturation (TSAT), transferrin) and CVD-RFs among women, and (2) explore if these associations were modified by menopausal status. METHOD: Cross-sectional and longitudinal analyses including 2542 and 1482 women from CoLaus cohort, respectively. Multiple linear regression and multilevel mixed models were used to analyse the associations between Iron biomarkers and CVD-RFs. Variability of outcomes and iron markers between surveys was accessed using intraclass correlation (ICC). RESULTS: After multivariable adjustment, elevated serum ferritin levels were associated with increased insulin and glucose levels, while higher transferrin levels were linked to elevated glucose, insulin and total cholesterol, and systolic and diastolic blood pressure (p < 0.05). No association was observed between CVD-RFs and TSAT (p > 0.05). Iron biomarkers demonstrated low reliability across reproductive stages but exhibited stronger associations in the perimenopausal group. In longitudinal analysis, we found association only for transferrin with lower glucose levels [ß = - 0.59, 95% CI (- 1.10, - 0.08), p = 0.02] and lower diastolic blood pressure [ß = - 7.81, 95% CI (- 15.9, - 0.56), p = 0.04]. CONCLUSION: In cross-sectional analysis, transferrin was associated with several CVD-RFs, and the associations did not change according to menopausal status. Conversely, in the longitudinal analyses, changes in transferrin were associated only with lower glucose and diastolic blood pressure levels. These differences might stem from the substantial longitudinal variation of iron biomarkers, underscoring the need for multiple iron measurements in longitudinal analyses.

The complementary roles of iron and estrogen in menopausal differences in cardiometabolic outcomes.

Biological hormonal changes are frequently cited as an explanatory factor of sex and menopause differences in cardiometabolic diseases (CMD) and its associated risk factors. However, iron metabolism which varies between sexes and among women of different reproductive stages could also play a role. Recent evidence suggest that iron may contribute to CMD risk by modulating oxidative stress pathways and inflammatory responses, offering insights into the mechanistic interplay between iron and CMD development. In the current review, we provide a critical appraisal of the existing evidence on sex and menopausal differences in CMD, discuss the pitfall of current estrogen hypothesis as sole explanation, and the emerging role of iron in CMD as complementary pathway. Prior to menopause, body iron stores are lower in females as compared to males, but the increase during and after menopause, is tandem with an increased CMD risk. Importantly, basic science experiments show that an increased iron status is related to the development of type 2 diabetes (T2D), and different cardiovascular diseases (CVD). While epidemiological studies have consistently reported associations between heme iron intake and some iron biomarkers such as ferritin and transferrin saturation with the risk of T2D, the evidence regarding their connection to CVD remains controversial. We delve into the factors contributing to this inconsistency, and the limitation of relying on observational evidence, as it does not necessarily imply causation. In conclusion, we provide recommendations for future studies on evaluating the potential role of iron in elucidating the sex and menopausal differences observed in CMD.

Healthy ageing in a multi-ethnic population: A descriptive cross-sectional analysis from the HELIUS study.

OBJECTIVE: We investigated ethnic health disparities in the Healthy Life in an Urban Setting multi-ethnic cohort using the multidimensional Healthy Ageing Score. STUDY DESIGN: We conducted a cross-sectional analysis of the study baseline data (2011-2015) collected through questionnaires/physical examinations for 17,091 participants (54.8 % women, mean (SD) age = 44.5 (12.8) years) from South-Asian Surinamese (14.8 %), African Surinamese (20.5 %), Dutch (24.3 %), Moroccan (15.5 %), Turkish (14.9 %), and Ghanaian (10.1 %) origins, living in Amsterdam, the Netherlands. MAIN OUTCOME MEASURES: We computed the Healthy Ageing Score developed in the Rotterdam Study, which has seven biopsychosocial domains: chronic diseases, mental health, cognitive function, physical function, pain, social support, and quality of life. That score was used to discern between healthy, moderate, and poor ageing. We explored differences in healthy ageing by ethnicity, sex, and age group using multinomial logistic regression. RESULTS: The Healthy Ageing Score [overall: poor (69.0 %), moderate (24.8 %), and healthy (6.2 %)] differed between ethnicities and was poorer in women and after midlife (cut-off 45 years) across ethnicities (all p < 0.001). In the fully adjusted models in men and women, poor ageing (vs. healthy ageing) was highest in the South-Asian Surinamese [adjusted odds ratios (95 % confidence intervals)] [2.96 (2.24-3.90) and 6.88 (3.29-14.40), respectively] and Turkish [2.80 (2.11-3.73) and 7.10 (3.31-15.24), respectively] vs. Dutch, in the oldest [5.89 (3.62-9.60) and 13.17 (1.77-98.01), respectively] vs. youngest, and in the divorced [1.48 (1.10-2.01) and 2.83 (1.39-5.77), respectively] vs. married. Poor ageing was inversely associated with educational and occupational levels, mainly in men. CONCLUSIONS: Compared with those of Dutch ethnic origin, ethnic minorities displayed less healthy ageing, which was more pronounced in women, before and after midlife, and was associated with sociodemographic factors.

Development and external validation of a home-based risk predicTion modEl of natUral onseT of menopAuse -TEUTA.

OBJECTIVE: To develop and externally validate a 10-year risk prediction model of natural onset of menopause using ready-to-use predictors. DESIGN: Population-based prospective cohort study. PARTICIPANTS: Community-dwelling, premenopausal women aged 28 years and older enrolled in the Swiss (CoLaus) and Dutch (PREVEND) study. MAIN OUTCOME MEASURE: Incidence of self-reported natural menopause. MODEL DEVELOPMENT: Based on existing literature, 11 predictors were tested in this study. The CoLaus cohort was used to develop the model by applying the backward-elimination approach and Bayesian Model Averaging. Internal validation was performed by bootstrapping. External validation was performed using data from the PREVEND cohort and recalibrating the baseline survival estimate. C-statistic, calibration slopes, and expected/observed probabilities were calculated as measures of model internal and/or external performances. RESULTS: The final analysis included 750 and 1032 premenopausal women from the CoLaus and the PREVEND cohort, respectively. Among them, 445 (59%) from CoLaus and 387 (38%) from PREVEND experienced menopause over a median follow-up of 10.7 and 9 years, respectively. The final model included age, alcohol consumption, smoking status, education level, and systolic blood pressure. Upon external calibration in the PREVEND cohort, the model exhibited good discrimination, with a C-statistic of 0.888 and an expected/observed probability of 0.82. CONCLUSIONS: We present the first internally and externally validated prediction model of natural menopause onset using readily available predictors. Validation of our model to other populations is needed.

Utility of iron biomarkers in differentiating menopausal status: Findings from CoLaus and PREVEND.

AIM: To examine the association of iron biomarkers with menopausal status and assess whether these biomarkers can help differentiate menopausal status beyond age. METHODS: In this cross-sectional study we included 1679 women from the CoLaus and 2133 from the PREVEND cohorts, with CoLaus used as primary cohort and PREVEND for replication. Ferritin, transferrin, iron, and transferrin saturation (TSAT) were used to assess iron status. Hepcidin and soluble transferrin receptor were assessed only in PREVEND. Menopausal status was self-reported and defined as menopausal or non-menopausal. Logistic regressions were used to explore the association of these iron biomarkers with menopause status. Sensitivity, specificity, area under the receiver operating characteristic curves (AUC), positive and negative predictive values as well as cut-off points for the iron biomarkers were calculated. The model with the highest AUC was defined as the best. RESULTS: In the CoLaus and PREVEND cohorts, respectively, 513 (30.6 %) and 988 (46.3 %) women were postmenopausal. Ferritin (OR, 2.20; 95 % CI 1.72-2.90), transferrin (OR, 0.03; 95 % CI 0.01-0.10), and TSAT (OR, 1.28; 95 % CI 1.06-1.54) were significantly associated with menopausal status in CoLaus, with the findings replicated in PREVEND. AUC of age alone was 0.971. The best model resulted from combining age, ferritin, and transferrin, with an AUC of 0.976, and sensitivity and specificity of 87.1 % and 96.5 %, respectively. Adding transferrin and ferritin to a model with age improved menopause classification by up to 7.5 %. In PREVEND, a model with age and hepcidin outperformed a model with age, ferritin, and transferrin. CONCLUSION: Iron biomarkers were consistently associated with menopausal status in both cohorts, and modestly improved a model with age alone for differentiating menopause status. Our findings on hepcidin need replication.

Psychiatric co-morbidities and cardiovascular risk factors in people with lifetime history of epilepsy of an urban community.

OBJECTIVES: Depression has been consistently reported in people with epilepsy. Several studies also suggest a higher burden of cardiovascular diseases. We therefore analysed psychosocial co-morbidity and cardiovascular risk factors in patients with a lifetime history of epilepsy in the PsyCoLaus study, a Swiss urban population-based assessment of mental health and cardiovascular risk factors in adults aged between 35 and 66 years. PATIENTS AND METHODS: Among 3719 participants in the PsyCoLaus study, we retrospectively identified those reporting at least 2 unprovoked seizures, defined as epilepsy. These subjects were compared to all others regarding psychiatric, social, and cardiovascular risk factors data using uni- and multivariable assessments. RESULTS: A significant higher need for social help (p<0.001) represented the only independent difference between 43 subjects with a history of epilepsy and 3676 controls, while a higher prevalence of psychiatric co-morbidities (p=0.015) and a lower prevalent marital status (p=0.01) were only significant on univariate analyses. Depression and cardio-vascular risk factors, as well as educational level and employment, were similar among the groups. CONCLUSIONS: This analysis confirms an increased prevalence of psychosocial burden in subjects with a lifetime history of epilepsy; conversely, we did not find a higher cardiovascular risk. The specific urban and geographical location of our cohort and the age span of the studied population may account for the differences from previous studies.

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome.

BACKGROUND: Cardiovascular diseases and their associated risk factors remain the main cause of mortality in western societies. In order to assess the prevalence of cardiovascular risk factors (CVRFs) in the Caucasian population of Lausanne, Switzerland, we conducted a population-based study (Colaus Study). A secondary aim of the CoLaus study will be to determine new genetic determinants associated with CVRFs. METHODS: Single-center, cross-sectional study including a random sample of 6,188 extensively phenotyped Caucasian subjects (3,251 women and 2,937 men) aged 35 to 75 years living in Lausanne, and genotyped using the 500 K Affymetrix chip technology. RESULTS: Obesity (body mass index > or = 30 kg/m2), smoking, hypertension (blood pressure > or = 140/90 mmHg and/or treatment), dyslipidemia (high LDL-cholesterol and/or low HDL-cholesterol and/or high triglyceride levels) and diabetes (fasting plasma glucose > or = 7 mmol/l and/or treatment) were present in 947 (15.7%), 1673 (27.0%), 2268 (36.7%), 2113 (34.2%) and 407 (6.6%) of the participants, respectively, and the prevalence was higher in men than in women. In both genders, the prevalence of obesity, hypertension and diabetes increased with age. CONCLUSION: The prevalence of major CVRFs is high in the Lausanne population in particular in men. We anticipate that given its size, the depth of the phenotypic analysis and the availability of dense genome-wide genetic data, the CoLaus Study will be a unique resource to investigate not only the epidemiology of isolated, or aggregated CVRFs like the metabolic syndrome, but can also serve as a discovery set, as well as replication set, to identify novel genes associated with these conditions.

Dietary counseling improves patient outcomes: a prospective, randomized, controlled trial in colorectal cancer patients undergoing radiotherapy.

PURPOSE: To investigate the impact of dietary counseling or nutritional supplements on outcomes in cancer patients: nutritional, morbidity, and quality of life (QoL) during and 3 months after radiotherapy. PATIENTS AND METHODS: A total of 111 colorectal cancer outpatients referred for radiotherapy, stratified by staging, were randomly assigned: group 1 (G1; n = 37), dietary counseling (regular foods); group 2 (G2; n = 37), protein supplements; and group 3 (G3; n = 37), ad libitum intake. Nutritional intake (diet history), status (Ottery's Subjective Global Assessment), and QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0) were evaluated at baseline, at the end, and 3 months after radiotherapy. RESULTS: At radiotherapy completion, energy intake increased in G1/G2 (P < or = .04), G1 more than G2 (P = .001), and decreased in G3 (P < .01). Protein intake increased in G1/G2 (P < or = .007), G1 less than G2 (not significant), and decreased in G3 (P < .01). At 3 months, G1 maintained nutritional intake and G2/G3 returned to baseline. After radiotherapy and at 3 months, rates of anorexia, nausea, vomiting, and diarrhea were higher in G3 (P < .05). At radiotherapy completion, in G1 all QoL function scores improved proportionally to adequate intake or nutritional status (P < .05); whereas in G2 only three of six function scores improved proportionally to protein intake (P = .04), and in G3 all scores worsened (P < .05). At 3 months, G1 patients maintained/improved function, symptoms, and single-item scores (P < .02); in G2, only few function and symptom scales improved (P < .05); in G3, QoL remained as poor as after radiotherapy. In G1/G2, respectively, improvement/deterioration of QoL correlated with better or poorer intake or nutritional status (P < .003). CONCLUSION: During radiotherapy, both interventions positively influenced outcomes; dietary counseling was of similar or higher benefit, whereas even 3 months after RT, it was the only method to sustain a significant impact on patient outcomes.

Cancer: disease and nutrition are key determinants of patients' quality of life.

GOALS OF WORK: The aims of this study were (1) to evaluate quality of life (QoL), nutritional status and dietary intake taking into account the stage of disease and therapeutic interventions, (2) to determine potential interrelationships, and (3) to quantify the relative contributions of the cancer, nutrition and treatments on QoL. PATIENTS AND METHODS: In this prospective cross-sectional study conducted in 271 head and neck, oesophagus, stomach and colorectal cancer patients, the following aspects were evaluated: QoL (EORTC-QLQ C30), nutritional status (percent weight loss over the previous 6 months), usual diet (comprehensive diet history), current diet (24-h recall) and a range of clinical variables. MAIN RESULTS: Usual and current intakes differed according to the site of the tumour ( P=0.02). Patients with stage III/IV disease showed a significant reduction from their usual energy/protein intake ( P=0.001), while their current intakes were lower than in patients with stage I/II disease ( P=0.0002). Weight loss was greater in patients with stage III/IV disease than in those with stage I/II disease ( P=0.001). Estimates of effect size revealed that QoL function scores were determined in 30% by cancer location, in 20% by nutritional intake, in 30% by weight loss, in 10% by chemotherapy, in 6% by surgery, in 3% by disease duration and in 1% by stage of disease. Likewise in the case of symptom scales, 41% were attributed to cancer location, 22% to stage, 7% to nutritional intake, 7% to disease duration, 4% to surgery, 1% to weight loss and 0.01% to chemotherapy. Finally for single items, 30% were determined by stage, 20% by cancer location, 9% by intake, 4% by surgery, 3% by weight loss, 3% by disease duration and 1% by chemotherapy. CONCLUSIONS: Although cancer stage was the major determinant of patients' QoL globally, there were some diagnoses for which the impact of nutritional deterioration combined with deficiencies in nutritional intake may be more important than the stage of the disease process.